Psychosocial hypertension develops in mice that compete in groups of 32 males and females in complex population cages (Circ Res 36: 156-164, 1975). At first reversible, it gradually becomes fixed. Progressive arteriosclerosis leads to myocardial fibrosis. An interstitial nephritis also develops. As many as 20% of males die in uremia by 6-9 months. In studies of 15 colonies we hve established that caffeine even at a dose of 3 mg/kg/day will lead to an increased incidence of renal disease in socially stressed mice, but has much less effect on nonstressed animals. The mechanism by which renal failure develops is not clear but it may be immunological and immune complex deposition or antitubular basement antibodies may be involved. Studies with Captopril (SQ 14225) indicate that the progression of renal damage with chronic elevation of blood pressure may be connected with elevated renin levels. Our current goal is to determine how caffeine accelerates deterioration of the kidneys of animals exposed to social stress. We plan to continue using the beta blocker Metoprolol with and without the vasodilator Spresoline, since the beta blocker alone does not give protection despite control of blood pressure. Preliminary work suggests that when Apresoline is added to the beta blocker, damage is far less. These studies will be combined with collaborative work on the immunological changes. The past five years of study have established that caffeine accelerates cardiorenal damage when combined with social stress. The work has now moved to the mechanisms involved, including possible immunological changes, and to methods of preventing them.